DE60317537T2 - PREOPERATIVE TREATMENT OF BREAST CANCER - Google Patents

Abstract

Neoadjuvant treatment of inflammatory or T3 to T4 breast cancer is carried out by administering to such patients a number of cycles of chemotherapy treatment in which DPPE first is administered followed by a combination of anthracyclines and taxanes.

Description

FIELD OF THE INVENTION

The The present invention relates to the treatment of breast cancer.

BACKGROUND OF THE INVENTION

A The most important chemotherapeutic treatments is one of malignant growth (cancer) in humans. The goal of chemotherapy is the complete one Eradication of clonogenic tumors or malignant cells at least impairment of the patient. One of the main limitations of a chemotherapeutic Approach to dealing with human cancer is in the general inability anticancer agents between normal cells and tumor cells differ. Antineoplastic agents have the least therapeutic Indices of all drug classes used in humans and thus generate significant and potentially life-threatening toxicities. Certain often used antineoplastic agents have specific for specific tissue and acute toxicities on. For example, vinca alkaloids have significant toxicity to nerve tissue on, while Adriamycin a specific toxicity for heart tissue and bleomycin for lung tissue exhibit. In general, almost all members of the major categories of antineoplastic agents have considerable toxicities to normal Cells of gastrointestinal, epidermal and myelopoietic Tissues on.

in the In general, the toxicity which antineoplastic agents for the pluripotent stem cells of myelopoietic tissue, the dose-limiting aspect for the chemical control of cancer in humans. This toxicity is due to that most anticancer agents are preferably against proliferating Cells act, but with no significant ability, between dividing normal tissue and dividing tumor tissue differ.

In certain types of locally advanced breast cancer, in particular Inflammatory or T3 to T4 breast cancer, is pre-operative Removal of the tumor applied a treatment with chemotherapeutic agents, to reduce the tumor size. T3 tumors are tumors of size> 3 and <4 cm. T3 tumors can dependent on of where the tumors are in the chest, operable or inoperable be. For example, they are often inoperable when they are close located on the chest wall, especially on small breasts. T4 tumors are tumors with a size of> 4 cm and are general inoperable. Inflammatory breast cancer infiltrates the lymphatics the skin, is common a diffuse tumor and highly malignant.

In the U.S. Pat. Nos. 6,288,799 . 5,859,065 . 5,708,329 . 5,747,543 and 5,618,846 , the University of Manitoba, describes an improved method for the in vivo chemotherapeutic treatment of cancer which comprises first administering a compound which inhibits normal cell proliferation while promoting malignant cell proliferation, in particular an effective antagonist selective for intracellular histamine receptors, in an amount sufficient to inhibit the binding of intracellular histamine to the receptors in normal and malignant cells. After a sufficient period of time to inhibit intracellular histamine binding, a chemotherapeutic agent is administered. There is obtained an improved toxic effect on the cancer cells from the chemotherapeutic agent, while any adverse effect of the chemotherapeutic agent on normal cells, especially bone marrow cells and gastrointestinal cells, is significantly improved. A useful compound that inhibits normal cell proliferation while promoting malignant cell proliferation is N, N-diethyl-2- [4- (phenylmethyl) phenoxy] ethanamine, herein abbreviated as DPPE.

SUMMARY OF THE INVENTION

It was surprisingly found in a Phase II clinical trial that that in the above mentioned Patents, if a combination of an antacyclin chemotherapeutic agent and a taxane therapeutic is used, an effective method for neoadjuvant treatment of represents inflammatory breast cancer or T3 to T4 breast cancer. additionally does that Procedure for a postoperative long-term survival.

wobei X und Y jeweils Fluor, Chlor oder Brom sind, Z eine Alkylengruppe aus 1 bis 3 Kohlenstoffatomen oder =C=O ist oder die Phenylgruppen so verbunden sind, dass ein Dreiringsystem gebildet wird, o und p 0 oder 1 sind, R₁ und R₂ jeweils eine Alkylgruppe sind, die 1 bis 3 Kohlenstoffatome enthält, oder so miteinander verbunden sind, dass ein Heterozyklus mit dem Stickstoffatom gebildet wird, und n 1, 2 oder 3 ist, oder pharmazeutisch annehmbarer Salze davon, und der Kombination eines Anthracyclin-Chemotherapeutikums und eines Taxan-Chemotherapeutikums bei der Herstellung eines Medikaments zur neoadjuvanten Chemotherapie menschlicher Patienten mit inflammatorischem Brustkrebs oder T3- oder T4-Brustkrebs, indem die Patienten einer Vielzahl von Chemotherapiezyklen in zuvor festgelegten Zeitabständen unterzogen werden bis das Krebsgewebe sich auf eine operable Größe verringert hat oder in Remission ist, wobei jeder Zyklus umfasst:

• (a) zunächst das Verabreichen der mindestens einen Diphenylverbindung an den Patienten, und,
• (b) nach einer ausreichenden Zeitdauer zur Ermöglichung einer Inhibierung der Bindung von intrazellulärem Histamin, das nachfolgende Verabreichen der Kombination von Chemotherapeutika an den Patienten.

The present invention thus provides the use of at least one diphenyl compound of the formula:

wherein X and Y are each fluoro, chloro or bromo, Z is an alkylene group of 1 to 3 carbon atoms or = C = O, or the phenyl groups are linked to form a three ring system, o and p are 0 or 1, R ₁ and R _{2 are} each an alkyl group containing 1 to 3 carbon atoms or joined together to form a heterocycle with the nitrogen atom, and n is 1, 2 or 3, or pharmaceutically acceptable salts thereof, and the combination of an anthracycline Chemotherapeutic agent and a taxane chemotherapeutic agent in the manufacture of a medicament for neoadjuvant chemotherapy of human patients with inflammatory breast cancer or T3 or T4 breast cancer by subjecting the patient to a variety of chemotherapy cycles at predetermined intervals until the cancerous tissue has decreased to an operable size or in remission, each cycle comprising:

• (a) first administering the at least one diphenyl compound to the patient, and,
• (b) after allowing sufficient time to allow inhibition of intracellular histamine binding, then administering the combination of chemotherapeutic agents to the patient.

In In the application of the present invention, the diphenyl compound and the chemotherapeutic agents generally by intravenous infusion administered. According to one preferred method is the patient a solution of the diphenyl compound while a desired one Period of time before administration of the chemotherapeutic agents and subsequently becomes a solution the chemotherapeutic agents in combination with the diphenyl compound while the period of administration of the chemotherapeutic agents. if desired becomes a solution the diphenyl compound after completion of the administration of the chemotherapeutic agents for one desired Time interval administered to the side effects of administration of chemotherapeutic agents mitigate.

GENERAL DESCRIPTION OF THE INVENTION

In the present invention, a diphenyl compound which is an effective antagonist of histamine binding to the intracellular histamine receptor and administered in an amount sufficient to inhibit the binding of intracellular histamine to the intracellular binding site (H _IC ) in normal cells is used. Such compounds have a pKi of at least about 5, preferably at least about 5.5.

wobei X und Y jeweils Fluor, Chlor oder Brom sind, Z eine Alkylengruppe aus 1 bis 3 Kohlenstoffatomen oder =C=O ist, o und p 0 oder 1 sind, R₁ und R₂ jeweils eine Alkylgruppe sind, die 1 bis 3 Kohlenstoffatome enthält, oder so miteinander verbunden sind, dass ein Heterozyklus mit dem Stickstoffatom gebildet wird, und n 1, 2, oder 3 ist. Es können pharmazeutisch annehmbare Salze der Diphenylverbindungen eingesetzt werden.Specific active compounds useful in the present invention are diphenyl compounds of the formula:

wherein X and Y are each fluoro, chloro or bromo, Z is an alkylene group of 1 to 3 carbon atoms or = C = O, o and p are 0 or 1, R ₁ and R _{2 are} each an alkyl group containing 1 to 3 carbon atoms or joined together to form a heterocycle with the nitrogen atom, and n is 1, 2, or 3. It is possible to use pharmaceutically acceptable salts of the diphenyl compounds.

gebildet wird.Alternatively, the benzene rings may be linked to form a three-ring system according to the structure:

is formed.

eine Diethylaminogruppe, obwohl andere Alkylaminogruppen, wie Dimethylamino, und, in einer anderen bevorzugten Ausführungsform, eine Morpholinogruppe, eingesetzt werden können, obwohl andere Heterozyklusgruppen, wie Piperazino, einge setzt werden können. o und p sind üblicherweise 0, wenn Z eine Alkylengruppe ist und n kann 2 sein. In einer besonders bevorzugten Ausführungsform ist Z -CH₂-, n ist 2, o und p sind jeweils 0 und

ist eine Diethylaminogruppe. Diese Verbindung, nämlich N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamin, die in der Form der freien Base oder in der Form seines Hydrochloridsalzes oder eines anderen pharmazeutisch annehmbaren Salzes vorliegen kann, wird hierin als DPPE abgekürzt. Neben einer Methylengruppe, welche die Benzolringe verbindet, können andere Verbindungsgruppen, wie =C=O, eingesetzt werden. Die Benzolringe können neben den Halogenatomen mit anderen Substituenten, beispielsweise einer Imidazolgruppe, versehen sein.In a preferred embodiment, the group is

a diethylamino group, although other alkylamino groups, such as dimethylamino, and, in another be Preferred embodiment, a morpholino group, can be used, although other heterocycle groups, such as piperazino, can be used sets. O and p are usually 0 when Z is an alkylene group and n can be 2. In a particularly preferred embodiment, Z is -CH ₂ -, n is 2, o and p are each 0 and

is a diethylamino group. This compound, namely N, N-diethyl-2- [4- (phenylmethyl) phenoxy] ethanamine, which may be in the form of the free base or in the form of its hydrochloride salt or other pharmaceutically acceptable salt, is abbreviated herein as DPPE. In addition to a methylene group which connects the benzene rings, other compound groups, such as = C = O, can be used. The benzene rings may be provided with other substituents, for example an imidazole group, in addition to the halogen atoms.

The used in the present invention diphenyl compound administered to the patient in any suitable manner, as by an intravenous Injection of a solution of it in an aqueous one pharmaceutically acceptable vehicle. The diphenyl compound is during the patient a period of time prior to administration of the chemotherapeutic agents.

The Chemotherapeutic agents used herein are anthracyclines, preferably Doxorubicin and epirubicin; and taxanes, preferably taxol (trade name by Bristol-Myers Squibb for Paclitaxel) and Taxoter (trademark of Aventis Pharma for docetaxel). The mixture of chemotherapeutic agents will in some way, with their normal administration in the conventional Breast cancer therapy is used, usually by an intravenous infusion a solution from that.

The Administration of the diphenyl compound to the patient before administration The chemotherapeutic agent is required to allow the diphenyl compound the binding of intracellular Histamine can inhibit in normal and malignant cells and as As a result, the proliferation of normal cells shuts down Proliferation of malignant cells, however, increased.

The Duration of administration of the diphenyl compound before administration the chemotherapeutic agent hangs of the diphenyl compound, its mode of administration and the size of the patient from. In general, the diphenyl compound is given to the patient for about 30 to about 90 minutes, preferably about 60 minutes, prior to administration the chemotherapeutic agents administered.

The Amount of diphenyl compound administered to the patient depends on the mitigating side effects, but should at least for Inhibition of intracellular histamine binding in normal cells be enough. The required amount to the advantageous Achieving effects of the present invention depends on the diphenyl compound used, the chemotherapeutic agents used and the amount of these funds used.

In general, the amount of diphenyl compound used in humans is about 8 to about 320 mg / M ^{2 of} the human to which the diphenyl compound is administered, with about 8 and 240 mg / M ^{2 being} the optimal dose for gastrointestinal protection. Above this dose range, the present invention is able to achieve an improved chemotherapeutic effect on breast cancer cells, while at the same time, in a variety of cases, traditional chemotherapy results in damage to normal cells or tissues not involved in the disease process. from damage by the chemotherapeutic agents.

In the neoadjuvant treatment of inflammatory or T3-bis T4 breast cancer, the diphenyl compound is preferably in a Amount of about 3 to about 10 mg / kg of the patient used intravenous while a period of about 30 to about 90 minutes before administration the chemotherapeutic agent is administered, and for the period of administration of the chemotherapeutic agent. As described herein specific phase II clinical trial 6 mg / kg of DPPE was used in the form of its hydrochloride salt, this intravenously as watery solution of it during 80 minutes, with the last 20 minutes of the Infusion of the chemotherapeutic agents were followed, followed by the intravenous Administration of an aqueous solution with a dose of 2.5 mg / kg of DPPE for 180 minutes, accompanied by the infusion of Taxol, or for 60 minutes, accompanied by the infusion of Taxoter.

One second regime for the DPPE / Taxoter treatment is the intravenous administration of an aqueous solution from DPPE for 80 minutes, taking the last 20 minutes of the infusion of the Taxoters followed by infusion of the Taxoters alone for 40 minutes.

The chemotherapeutic agents employed herein are preferably employed in a total amount of from 75 to about 225 mg / M ^{2 of} the patient, consistent with the identity of the chemotherapeutic agent. The chemotherapeutic agents may be administered in an amount of about 50 to about 60 mg / M ^{2 of} the patient for doxorubicin or epirubicin, about 175 to about 225 mg / M ² taxol, and about 75 to about 100 mg / M ² taximeters. In the particular phase II clinical study described herein, 50 mg / M ² doxorubicin or epirubicin and 175 mg / M ² taxol or 75 mg / M ² taxotere were used during the last 20 minutes of the DPPE solution infusion and during further 180 minutes for Taxol or 60 minutes for Taxoter, accompanied by infusion of a 2.5 mg / kg DPPE solution.

As mentioned above, Patients with inflammatory breast cancer or T3-up T4 breast cancer of a number of chemotherapy cycles in previously defined intervals subjected to the size of the tumor to reduce to an operable size. The number of cycles for every patient is generally about 5 to about 8 cycles, with about 21 to 28 days between each cycle. In the clinical phase II study Patients underwent 6 cycles at 21 day intervals.

As set forth herein has been a clinical phase II study with patients performed with inflammatory or T3 to T4 breast cancer, in which was administered DPPE to the patient, followed by doxorubicin or epirubicin and Taxol or Taxoter. Various data of the clinical Study were recorded and analyzed.

The Results of this study showed that DPPE together with doxorubicin / epirubicin and Taxol / Taxoter was an effective neoadjuvant treatment, which led to a postoperative long-term survival.

EXAMPLE

This Example illustrates the neoadjuvant treatment of inflammatory or T3-T4 breast cancer.

A Phase II clinical trial was conducted in patients with N = 8 (N = 7) and T3-T4 (N = 1) breast cancers with a combination of DPPE and epirubicin (EPI / Taxol (N = 5), a combination of DPPE and doxorubicin (DOX) / taxol (N = 2) and DPPE and a combination of DPPE and epirubicin / taxoter (N = 1) DPPE was administered at a dose of 6 mg / M ² during 80 minutes with a combination of epirubicin or doxorubicin at a dose of 50 mg / M ² and taxol at a dose of 175 mg / M ² or taxotere at a dose of 75 mg / M ² during the last 20 minutes, and a further 180 minutes for Taxol or 60 minutes for Taxoter at a dose of 2.5 mg / kg The treatment was repeated at intervals of 21 days for 6 cycles The eight patients with inflammatory or T3 to T4 breast cancer had no previous chemo or Radiotherapy After completing the chemotherapy cycles, the cancerous tissue was removed and the patients are watching.

The The results obtained are shown in Table 1. In this table is the abbreviation TTP for the Time to progression and the abbreviation OS stands for the overall survival. Two long-term survivors (45+ and 53+ months) had a mixed high-grade tumor pretreatment, however no postoperative high-grade component. A third patient with only high-grade cells or cytology, showed a complete clinical / pathological Remission. This patient remained disease free at 55+ months.

These Findings are consistent with those in the co-pending US application No. 60 / 331,242 filed November 9, 2001 in the name of Lorne Brandes and Mark Vincent proposed a DPPE-based chemotherapy hypothesis primarily preferentially on malignant high-grade cell populations directed.

SUMMARY OF THE INVENTION

• ^†5 DPPE/EPI/TAXOL; 2 DPPE/DOX/TAXOL; 1 DPPE/EPI/TAXOTER
• *Pathologische Kriterien

In summary of this disclosure, the present invention provides a neoadjuvant chemotherapeutic treatment of inflammatory or T3 to T4 breast cancer. TABLE 1 SUMMARY OF THE RESULTS OF NEOADJUVANT THERAPY No patients Cycles (total) Answer* TTP OS (Mean, mth.) CR PR NO 8 ^† 46 The 4/2 * 3/4 * 1/2 * 21 43+

• ^† 5 DPPE / EPI / TAXOL; 2 DPPE / DOX / TAXOL; 1 DPPE / EPI / TAXOTER
• * Pathological criteria

Claims (9)

Use of at least one diphenyl compound of the formula

wherein X and Y are each fluoro, chloro or bromo, Z is an alkylene group of 1 to 3 carbon atoms or = C = O, or the phenyl groups are linked to form a three ring system, o and p are 0 or 1, R ₁ and R _{2 are} each an alkyl group containing 1 to 3 carbon atoms or joined together to form a heterocycle with the nitrogen atom, and n is 1, 2 or 3, or pharmaceutically acceptable salts thereof, and the combination of an anthracycline Chemotherapeutic agent and a taxane chemotherapeutic agent in the manufacture of a medicament for neoadjuvant chemotherapy of human patients with inflammatory breast cancer or T3 or T4 breast cancer by subjecting the patient to a variety of chemotherapy cycles at predetermined intervals until the cancerous tissue has decreased to an operable size or in remission, each cycle comprising: (a) first administering the at least one D (b) after a sufficient period of time to allow inhibition of intracellular histamine binding, subsequent administration of the combination of chemotherapeutic agents to the patient. Use according to claim 1, wherein the group

a diethylamino group, a dimethylamino group, a morpholino group or a piperazino group, preferably a diethylamino group, in which case Z is -CH ₂ , n is 2 and o and p are each 0, optionally in the form of a hydrochloride salt. Use according to claim 1 or 2, wherein the anthracycline chemotherapeutic agent Doxorubicin or epirubicin is. Use according to any one of claims 1 to 3, wherein the taxane chemotherapeutic agent Taxol or Taxoter is. Use according to any one of claims 1 to 4, wherein the diphenyl compound the patient 30 to 90 minutes, preferably 60 minutes, before the Administration of the combination of chemotherapeutic agents is, preferably by intravenous infusion of a solution of Diphenyl compound over a period of up to 90 minutes prior to the administration of the chemotherapeutic agents, and while the administration of the combination of chemotherapeutic agents is, more preferably by administering the diphenyl compound for 60 Minutes before administration of the combination of chemotherapeutic agents and wherein the administration during the intravenous Infusion of the combination of chemotherapeutic agents is maintained. Use according to claim 5, wherein the administration the taxane chemotherapeutic, optionally in combination with the anthracycline chemotherapeutic agent, while 20 minutes while maintaining the infusion of the diphenyl compound followed by continued infusion of the diphenyl compound for the rest administration of the taxane chemotherapeutic agent. Use according to any one of claims 1 to 6, wherein the diphenyl compound is administered in an amount of 8 to 240 mg / M ^{2 of} the patient, preferably 3 to 10 mg / kg of the patient, more preferably 6 mg / kg. Use according to any one of claims 1 to 7, wherein the combination of chemotherapeutic agents in an amount of 50 to 60 mg / M ² , preferably 50 mg / M ² , of the patient for doxorubicin and epirubicin, 175 to 225 mg / M ² , preferably 175 mg / M ² , for taxol and 75 to 100 mg / M ² , preferably 75 mg / M ² , for Taxoter. Use according to any one of claims 1 to 8, wherein the number of cycles of chemotherapeutic treatment is 5 to 10, the at intervals be administered from 21 to 28 days.